ABSTRACT The debilitating ultrarare skin disorder pachyonychia congenita (PC) affects less than 10,000 patients worldwide and is caused by dominant mutations in the inducible keratins (KRT) including KRT6a, 6b, 16 and 17. We discovered that the 5' untranslated regions of KRT6a and 6b transcripts contain a regulatory motif that confers sensitivity to sirolimus and other mTOR inhibitors. mTOR inhibitors also potently inhibit phosphorylation of mTOR pathway components such as ribosomal protein S6 (rpS6). We postulate that KRT6a/b gene expression is a downstream target of the mTOR pathway and we demonstrated KRT6a gene inhibition at the level of mRNA translation following sirolimus treatment in human keratinocyte cultures. Furthermore, we identified that the mTOR signaling pathway is activated in PC lesions compared to adjacent unaffected skin in patient biopsies. Based on these preclinical data, we initiated a small off-label study of orally administered Rapamune (Pfizer) in three PC patients, which resulted in marked improvement of PC symptoms including plantar pain. Unfortunately, all of the participating patients suffered from the well-known side effects associated with systemic oral sirolimus exposure. To avoid the adverse events associated with oral sirolimus administration, we propose to treat PC lesions directly with a topical formulation to achieve high drug levels at the site where needed, minimizing systemic exposure. To this end, we propose a Phase 1b clinical trial in PC patients with a proprietary topical sirolimus formulation (TD201) developed at TransDerm. This formulation readily penetrates human skin and delivers functional inhibitor to mouse skin as exhibited by rpS6 phosphorylation inhibition. This TD201 study is a prospective, randomized, double-blinded, split-body, placebo-controlled Phase 1b safety study with secondary efficacy objectives that has been approved by the FDA and by the Stanford Institutional Review Board. Therefore, this clear regulatory path, coupled with the availability of clinical Rapamune from the manufacturer Pfizer and their agreement to allow cross-referencing of their CMC and toxicity packages, suggests that clinical evaluation of TD201 is highly feasible with no major obstacles to move forward. Importantly, the FDA granted TransDerm orphan drug designation to treat PC patients with sirolimus, independent of the route of drug delivery. The demonstration that topical sirolimus is effective and safe, and has fewer side effects when compared to systemic sirolimus administration, should pave the way for approval for topical sirolimus treatment of a host of other disorders resulting from an activated mTOR pathway including scarring associated with laser treatment of port wine stain birthmarks, angiofibromas in tuberous sclerosis complex and possibly psoriasis and squamous cell carcinoma.